Cellular & molecular immunology, 2021-01, Vol.18 (1), p.162-170
2021
Details
- Autor(en) / Beteiligte
- Titel
- Suppression of monosodium urate crystal-induced inflammation by inhibiting TGF-β-activated kinase 1-dependent signaling: role of the ubiquitin proteasome system
- Ist Teil von
- Cellular & molecular immunology, 2021-01, Vol.18 (1), p.162-170
- Ort / Verlag
- China: Nature Publishing Group
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Monosodium urate (MSU) crystals activate inflammatory pathways that overlap with interleukin-1β (IL-1β) signaling. However, the post-translational mechanisms involved and the role of signaling proteins in this activation are unknown. In the present study, we investigated the intracellular signaling mechanisms involved in MSU-induced activation of THP-1 macrophages and human nondiseased synovial fibroblasts (NLSFs) and the in vivo efficacy of an inhibitor of tumor growth factor-β (TGF-β)-activated kinase 1 (TAK1), 5Z-7-oxozeaenol, in MSU-induced paw inflammation in C57BL/6 mice. THP-1 macrophage activation with MSU crystals (25-200 µg/ml) resulted in the rapid and sustained phosphorylation of interleukin-1 receptor-activated kinase 1 (IRAK1 Thr ) and TAK1 (Thr ) and their association with the E3 ubiquitin ligase TRAF6. At the cellular level, MSU inhibited the deubiquitinases A20 and UCHL2 and increased 20s proteasomal activity, leading to a global decrease in K -linked ubiquitination and increase in K -linked ubiquitination in THP-1 macrophages. While MSU did not stimulate cytokine production in NLSFs, it significantly amplified IL-1β-induced IL-6, IL-8, and ENA-78/CXCL5 production. Docking studies and MD simulations followed by TAK1 in vitro kinase assays revealed that uric acid molecules are capable of arresting TAK1 in an active-state conformation, resulting in sustained TAK1 kinase activation. Importantly, MSU-induced proinflammatory cytokine production was completely inhibited by 5Z-7-oxozeaenol but not IRAK1/4 or TRAF6 inhibitors. Administration of 5Z-7-oxozeaenol (5 or 15 mg/kg; orally) significantly inhibited MSU-induced paw inflammation in C57BL/6 mice. Our study identifies a novel post-translational mechanism of TAK1 activation by MSU and suggests the therapeutic potential of TAK1 in regulating MSU-induced inflammation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1672-7681eISSN: 2042-0226DOI: 10.1038/s41423-019-0284-3Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7853128
- Format
- –
- Schlagworte
- Animals, Antioxidants - toxicity, Cell activation, Conformation, Crystals, Cytokines, Fibroblasts, Fibroblasts - drug effects, Fibroblasts - metabolism, Fibroblasts - pathology, Gout - chemically induced, Gout - drug therapy, Gout - enzymology, Gout - pathology, Humans, IL-1β, Inflammation, Inflammation - chemically induced, Inflammation - drug therapy, Inflammation - enzymology, Inflammation - pathology, Interleukin 1, Interleukin 6, Interleukin 8, Intracellular signalling, IRAK protein, Lactones - pharmacology, Macrophages, Male, MAP Kinase Kinase Kinases - antagonists & inhibitors, Mice, Mice, Inbred C57BL, Phosphorylation, Post-translation, Proteasome Endopeptidase Complex - drug effects, Proteasomes, Resorcinols - pharmacology, Signal Transduction, Synovial Membrane - drug effects, Synovial Membrane - metabolism, Synovial Membrane - pathology, TAK1 protein, TRAF6 protein, Transforming Growth Factor beta - genetics, Transforming Growth Factor beta - metabolism, Translation, Ubiquitin, Ubiquitin - metabolism, Ubiquitin-protein ligase, Ubiquitination, Uric acid, Uric Acid - toxicity